Pharmacodynamic Similarity to Prenylamine

PHARMACODYNAMIC SIMILARITY TO PRENYLAMINE

Terodiline also resembles prenylamine in terms of pharmacodynamic activity. Both have complex phar-macodynamic effects that are stereoselective and are active at multiple channels. Some aspects of this simi-larity had been pointed out as long ago as 1983 (Fleckenstein, 1983).

Although prenylamine has been described as a calcium antagonist, it is not a true calcium channel blocker since it does not act selec-tively at the membrane-associated, voltage-dependent calcium channels. However, it is a potent inhibitor of calmodulin-dependent enzymes, relaxes smooth muscle and reduces slow inward current. In addition, it depresses peak sodium conductance (Hashimoto et al., 1978; Bayer, Schwarzmaier and Pernice, 1988). Hashimoto et al. (1978) have also shown that preny-lamine increases action potential duration, indicating that the drug may interfere with the late outward repo-larizing current mediated by potassium ions. Thus, in addition to its negative inotropic effect, prenylamine most probably has sodium and potassium channel blocking activities. More recently, prenylamine has been shown conclusively to block the potassium chan-nel that is primarily responsible for cardiac repolar-ization (Katchman et al., 2006).

With regard to stereoselective pharmacodynamic effects, (+) -(S)-prenylamine has a positive inotropic effect in cat papillary muscle preparations that is particularly evident at low concentrations, and at low stimulation rates (Bayer, Schwartzmaier and Pernice, 1988). The maximum velocity of depolarization is somewhat increased by both (+) -(S)-prenylamine and the racemic mixture at low concentrations. (−) -(R)-prenylamine is associated with a negative inotropic effect and a decrease in the maximum velocity of depolarization. As far as cardiac repolarization is concerned, (+) -(S)-prenylamine prolonged the action potential duration and induced arrhythmia in 4 of the 12 isolated papillary muscle preparations. In contrast, the (−) -(R)-isomer shortened the action potential duration to a minor extent. This effect was independent of stimulation rates but evident at low concentrations.

Terodiline not only blocks the uptake of calcium, it also blocks the utilization of some intracellular stores of calcium. Pressler et al. (1995) have inves-tigated the in vitro and in vivo electrophysiological effects of terodiline, and have shown that it blocks sodium and calcium channels as well as muscarinic receptors in canine cardiac tissues. Terodiline has been shown to be a non-selective muscarinic receptor antagonist (Noronha-Blob et al., 1991), and therefore its anticholinergic effects on the heart are not alto-gether surprising. The primary pharmacological activ-ities of terodiline are potent calcium antagonistic and non-selective anticholinergic effects within the same clinical concentration range. Although both activities probably contribute to the therapeutic effect to a vari-able extent, the anticholinergic effect predominates at low concentrations and the calcium blocking action at high concentrations (Andersson, 1984). In another study in anaesthetized dogs, terodiline (10 mg/kg given intravenously) significantly prolonged the QTc interval by 6%–8%, an effect associated with induc-tion of torsade de pointes (Natsukawa et al., 1998). Like prenylamine, terodiline too has been shown to block the potassium channel responsible for cardiac repolarization (Jones et al., 1998).

The pharmacological activities of terodiline are also enantioselective. The effects of racemic terodiline on isolated detrusor preparations from rabbit and man were compared with those of its ((+) -(R)- and (−) -(S)-isomers, and with those of its main metabolite, p-hydroxy-terodiline (Andersson, Ekstrom and Matti-asson, 1988). It was concluded that (+) -(R)-terodiline is the main contributor of the detrusor effects of the racemate, and that a component of this activity is anti-cholinergic in nature. Whereas (+) -(R)-terodiline has been shown to be almost ten times more potent than -(S)-terodiline in its anticholinergic activity,  (−) -(S)-terodiline is almost ten times more potent than its antipode as a calcium antagonist (Larsson-Backstrom, Arrhenius and Sagge, 1985; Andersson, Ekstrom and Mattiasson, 1988).

Available data indicate that terodiline in low concentrations has mainly an anticholinergic action arising from the (+) -(R)-enantiomer, and as the concentration rises, additional calcium antagonis-tic effects from (−) -(S)-terodiline begin to emerge (Husted et al., 1980). Since in vitro data suggest that at high concentrations the metabolism of terodiline is stereoselective favouring the (+) -(R)-enantiomer (Noren et al., 1989), it seems likely that the dominant enantiomer circulating in human plasma at clinical doses of 25 mg is (+) -(R)-terodiline. As discussed below, this has significant implications in terms of the cardiac effects of terodiline.